tbuckley/cabot-search huggingface dataset:
Abstract 5127: Significance of Trop-2 in HER2-positive breast cancer
Authors: Chun-Yu Liu, Ji-Lin Chen, Pei-Yi Chu, Chun-Teng Huang, Wan-Lun Wang, Chi-Cheng Huang, Po-Han Lin, Ling-Ming Tseng
Journal: Cancer Research (2022)

Abstract Purpose: The glycoprotein Trop-2 is frequently overexpressed in human malignancies and linked to worse outcome. A Trop2-targeting antibody-drug conjugate, sacituzumab govitecan, has been approved by the FDA for patients with unresectable locally advanced or metastatic triple-negative breast cancer. Trop-2 enhances Akt phosphorylation in numerous cancer cell lines, while the opposite findings are also reported suggesting the cell context-dependent effect of Trop-2. Blockade of PI3K/Akt pathway mediates anti-tumor mechanism of anti-HER2 agents. In this study, we aim to investigate the role of Trop-2 in HER2-positive breast cancer. Experimental design: The archival samples comprising different breast cancer subtypes were analyzed using immunohistochemical staining. The public databases, including, Metabric, KM plotter, ROC plotter, were used to verify the prognostic role and clinical significance of Trop-2 in HER2-positive breast cancer. In vitro tumor models, the transwell migration, invasion and sphere assays, were applied for evaluation of cancer progression. The apoptotic cells were determined by flow cytometry using Annexin V/propidium iodide double staining. Results: We analyzed a cohort of 986 breast cancer patients and found that HER2-positive breast cancer harbored higher Trop-2 protein expression than other breast cancer subtypes. Higher levels of Trop-2 and phospho-Akt in HER2-positive breast cancer tissues compared with normal tissues. Trop-2 expression was correlated with tumor stage and phospho-Akt level. HER2-positive breast cancer patients with high level of Trop-2 protein were linked to worse recurrence-free survival. Consistently, data from the public databases exhibited patients with higher level of Trop-2 transcript had shorter recurrence-free survival and overall survival of HER2-positive breast cancer. Overexpression of Trop-2 increased cell migration, invasion and sphere number in SK-BR-3 and BT-474 cells. In contrast, knockdown of Trop-2 suppressed cell motility and sphere formation. Trop-2-expressing cells had better cell viability compared to control cells in the presence of lapatinib or neratinib treatment. Lapatinib- and neratinib-induced cell apoptosis was rescued by Trop-2 overexpression. Notably, patients responded to anti-HER2 therapy had lower Trop-2 transcript expression than non-responders. Conclusion: These results suggested that the oncogenic role of Trop-2 in HER2-positive breast cancer and Trop-2 expression might confer resistance to anti-HER2 therapy. Citation Format: Chun-Yu Liu, Ji-Lin Chen, Pei-Yi Chu, Chun-Teng Huang, Wan-Lun Wang, Chi-Cheng Huang, Po-Han Lin, Ling-Ming Tseng. Significance of Trop-2 in HER2-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5127.
Abstract 3364: Diagnosing Li-Fraumeni syndrome from the somatic genome
Authors: Brianne Laverty, Vallijah Subasri, Nicholas Light, David Malkin
Journal: Cancer Research (2022)

Abstract Background: Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in the tumor suppressor gene TP53. LFS is estimated to occur in 1:1000 - 1:5000 people and is associated with a 80% lifetime cancer risk. This syndrome is diagnosed using familial cancer history and germline TP53 sequencing; however, clinical heterogeneity and variants of unknown significance limit diagnostic precision. Accurate diagnosis is imperative to implement surveillance for secondary malignancies and familial genetic testing. Methods: We hypothesized that LFS cancers evolve uniquely from sporadic cancers, implying that the somatic genomes of LFS patients exhibit distinct characteristics that can infer the predisposition syndrome. To investigate this, we interrogated mutational signatures, TP53 copy number, TP53 loss of heterozygosity, ploidy, and the incidence of chromothripsis in tumor compared to normal samples (blood or fibroblast) of individuals with germline TP53 mutations (n=27), somatic TP53 mutations (n=17) and WT for TP53 (n=158). We created a random forest model with 10-fold cross validation to determine if somatic features could diagnose LFS. Results: No signatures were significantly associated with LFS (Wilcoxon rank-sum test, Benjamin-Hochberg FDR correction). As previously reported in the literature, LFS compared to non-LFS cancers in our cohort were more likely to: be hyperdiploid (odds ratio (OR) = 11.83, FDR &amp;lt; 0.0001, Fisher exact test), have undergone TP53 loss of heterozygosity (OR = 23.15, FDR &amp;lt; 0.0001, Fisher exact test) and experience chromothripsis (OR = 7.76, FDR &amp;lt; 0.001, Fisher exact test). The area under the receiver operating curve (AUROC) for our random forest model with 10-fold cross validation was 0.90, the area under the precision recall curve (AUPRC) was 0.59, the positive predictive value (PPV) was 0.70, the negative predictive value (NPV) was 0.93 and the F1-score was 0.52. This implies that the somatic genomic features are reliable indicators of this germline syndrome. We have obtained access to a future 50 LFS samples from the Pediatric Cancer Genome Project dataset, which we hope will improve our model’s performance. Conclusion: We have developed a machine learning tool that uses somatic features to identify LFS, a germline cancer predisposition syndrome. As the importance of precision oncology becomes apparent, a tool to identify LFS patients from the somatic genome will facilitate early diagnosis. This will allow individuals to enter a surveillance program for early detection of secondary tumors, leading to improved outcomes. Citation Format: Brianne Laverty, Vallijah Subasri, Nicholas Light, David Malkin. Diagnosing Li-Fraumeni syndrome from the somatic genome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3364.
Abstract LB506: Structure based small molecule drug design for targeting WNK1 in triple negative breast cancer
Authors: Ashari Rashmi Kannangara, Melanie Rodriguez, Julita Chlebowicz, Radha Akella, Melanie H. Cobb, Uttam Tambar, Elizabeth J. Goldsmith
Journal: Cancer Research (2022)

Abstract Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors lacking estrogen, progesterone, and HER-2 receptors. It accounts for 10-20% of breast cancers, appears in younger women, metastasizes fast, and is associated with poor prognosis and poor patient survival. There are no available tailored therapies for TNBC to date. One of the ways to treat TNBC is by targeting its metastasis feature. With-no-lysine kinase 1 (WNK1), which is known to interact with diverse signaling pathways including ion homeostasis, has been recently identified as one of 6 driver genes in a murine TNBC model. Published and preliminary data support the premise that WNK1 promotes epithelial-mesenchymal transition (EMT) and invasion in TNBC. Genetic and pharmacological inhibition of WNK1 blocks metastasis in a TNBC mouse model. Given the existence of four WNK isoforms in which kinase domains are 90% identical, developing a clinically available WNK1-specific inhibitor is an unmet need. We identified WNK1-selective inhibitors by a High Throughput Screen (HTS) of over 200,000 structurally diverse small molecules. A class of quinoline-derived compounds showed high specificity and potency for WNK1. A combination of molecular modeling, crystallography, and synthesis-based strategies were employed to improve the potency of compounds. Interestingly, the compound SC107-01 reported below 100 nM IC50 for WNK1 by in vitro assays. Also, it shows higher specificity for WNK1 over other kinases as evident by kinome-specificity profiling. We had previously crystallized the kinase domain of WNK1. The structure revealed its unique active site. Co-crystal structure of SC107-01 with WNK1 shows that the inhibitor binds to the WNKs’ specific active site and forms a unique set of interactions. Further modifications to the SC107-01 are underway to improve bioavailability and efficacy. In vivo toxicology and drug pharmacokinetics will be conducted in mouse models. We anticipate that this work will lay the foundation for developing a small molecule that inhibits WNK1 to combat metastasis in TNBC. Citation Format: Ashari Rashmi Kannangara, Melanie Rodriguez, Julita Chlebowicz, Radha Akella, Melanie H. Cobb, Uttam Tambar, Elizabeth J. Goldsmith. Structure based small molecule drug design for targeting WNK1 in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB506.
Abstract 5827: Increased miR150 expression in tumors enhances lymphocytes infiltration causing immunosuppression through inflammatory chemokines
Authors: Aparna Maiti, Masanori Oshi, Rongrong Wu, Nitai Hait, Kazuaki Takabe
Journal: Cancer Research (2022)

Abstract Dysregulated miRNAs play key roles in multiple biological processes and cancer. miR-150-5p, a cancer-related miRNA, has been reported to be aberrantly expressed in various cancers. We found that triple-negative and HER2+ breast cancer patients have elevated expression of miR150 in the TCGA and METABRIC patient cohort. Both cohorts showed significantly increased expression of miR150 in grade IV patients. Further studies explained that miR150 is strongly correlated with CD8+ T cells and B cells in accord with increased expression of immune-checkpoint markers PD-1, PDL-1, and CTLA4. We, therefore, hypothesized that higher expression of miR150 in tumors attracted more immune cells in the tumor microenvironment. We use two triple negative breast cancer cell lines MDA-231 and BT-549 cells and overexpressed miR150 followed by co-culture them with Jurkart and B cells. Our data revealed that both jurkart and B cells had increased migration towards cancer cells overexpressed miR150 mimic compared to miR150 mimic negative control. Interestingly, overexpressed miR150 mimic in cancer cells inhibited migration in both triple-negative breast cancer cells. Overexpression of miR150 mimic in cancer cells did not alter cell proliferation. To understand further the role of miR150 in breast cancer, we overexpressed miR150 mimic and its corresponding negative control in MDA-231 and did RNA seq analysis. RNA seq data explained that approximately 4927 genes are upregulated with miR150 mimic overexpression. Interestingly several chemokines and mediators of metastasis (CXCL2, CXCL1 CCL20, IGBP3, and ANGPTL4) are upregulated among the top 50 upregulated genes. In addition, gene enrichment analysis explained that TNF-α signaling pathways, Hypoxia, epithelial-mesenchymal pathways, E2F signaling, and Inflammatory pathways are a few upregulated pathways with miR150 mimic overexpression compared to the negative control. We also found miR150 high tumor enriched correlated with interferon-alpha and gamma signaling, inflammatory response pathways similar with cohort analysis data. In conclusion, miR150 in cancer plays a key role in interferon and inflammatory signaling pathways attracting more immune cells and suppressing the tumor microenvironment. Citation Format: Aparna Maiti, Masanori Oshi, Rongrong Wu, Nitai Hait, Kazuaki Takabe. Increased miR150 expression in tumors enhances lymphocytes infiltration causing immunosuppression through inflammatory chemokines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5827.
Abstract 3337: Preclinical activity of NVL-655 in ALK-driven cancer models beyond non-small cell lung cancer
Authors: Anupong Tangpeerachaikul, Ludovic Bigot, Luc Friboulet, Henry E. Pelish
Journal: Cancer Research (2022)

Abstract The ALK receptor tyrosine kinase can be aberrantly activated by gene fusions, point mutations, or amplification to promote cancer. ALK fusions are detected in approximately 5% of advanced non-small cell lung cancers (NSCLC), 50% of inflammatory myofibroblastic tumors, 50% of adult and 90% of childhood anaplastic large cell lymphomas, and rare cases of cholangiocarcinomas. Over 90 fusion partners of ALK have been identified, each exerting a different influence on the biochemical properties of the fusion protein and its preclinical sensitivity to ALK inhibitors. Besides fusions, ALK point mutations and amplification account for up to 14% and 2% of sporadic neuroblastomas, respectively, with most activating mutations occurring at residues F1174, F1245, or R1275. Some activating mutations, such as those occurring at F1174 and I1171, also confer resistance to FDA-approved ALK inhibitors. Because ALK plays an oncogenic role in diverse cancer types, it is an important therapeutic target for other indications beyond NSCLC. NVL-655 is a novel, brain-penetrant ALK-selective inhibitor that exhibits preclinical activity against ALK alterations, including resistance mutations, while also sparing inhibition of TRKB. TRKB inhibition in the central nervous system has been implicated in adverse events observed with FDA-approved ALK inhibitor lorlatinib. We previously reported the preclinical activity of NVL-655 in several NSCLC models bearing ALK-fusions, including human cell lines, a human cell-line derived xenograft, and a patient-derived xenograft. Here we report a broader characterization of NVL-655 in ALK-driven cancer models beyond NSCLC, alongside other ALK inhibitors that are either FDA-approved or in development. In biochemical assays, NVL-655 showed potent inhibition (IC50 &amp;lt; 10 nM) of ALK with mutations at residues 1151, 1174, or 1275, all of which have been identified in neuroblastoma. In cell-based assays, NVL-655 was observed to inhibit proliferation of a human anaplastic large cell lymphoma cell line harboring NPM1-ALK fusion and human neuroblastoma cell lines harboring ALK activating mutations or amplification. In conclusion, the preclinical profile of NVL-655 supports its potential to address a medical need for patients with ALK-driven disease in both NSCLC and other cancers such as anaplastic large cell lymphoma and neuroblastoma. Citation Format: Anupong Tangpeerachaikul, Ludovic Bigot, Luc Friboulet, Henry E. Pelish. Preclinical activity of NVL-655 in ALK-driven cancer models beyond non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3337.
Update June 2022: management of hospitalised adults with coronavirus disease 2019 (COVID-19): a European Respiratory Society living guideline
Authors: Nicolas Roche, Megan L. Crichton, Pieter C. Goeminne, Bin Cao, Marc Humbert, Michal Shteinberg, Katerina M. Antoniou, Charlotte Suppli Ulrik, Helen Parks, Chen Wang, Thomas Vandendriessche, Jieming Qu, Daiana Stolz, Christopher Brightling, Tobias Welte, Stefano Aliberti, Anita K. Simonds, Thomy Tonia, James D. Chalmers
Journal: European Respiratory Journal (2022)

Since the identification of SARS-CoV2 at the end of 2019, the COVID-19 pandemic has affected more than 410 million people worldwide and killed almost 6 million [1, 2]. The predecessors of COVID-19 ( i.e. , SARS for severe acute respiratory syndrome and MERS for Middle-East respiratory syndrom) had been relatively self-limiting, preventing clinicians and researchers from establishing evidence-based specific therapeutic strategies [3]. Conversely, COVID-19 rapidly proved to be extremely fast spreading, which led stakeholders to encourage, guide, build or fund multidirectional therapeutic research strategies based on both repurposing and development of new agents [4–8]. The authors wish to thank Kristel Paque and Krizia Tuand, the biomedical reference librarians of the KU Leuven Libraries – 2Bergen – learning Centre Désiré Collen (Leuven, Belgium), for their help in conducting the systematic literature search.
Abstract 5835: Functional and mechanistic characterization of ΔNp63α in esophageal squamous cell carcinoma
Authors: Shan Shan So, Valen Z. Yu, Simon Y. Law, Maria L. Lung
Journal: Cancer Research (2022)

Abstract Esophageal squamous cell carcinoma (ESCC) is highly prevalent in Asia with a poor prognosis and a high mortality rate [1, 2]. The p63 protein, encoded by TP63, is a master regulator involved in many cell events including cell cycle, DNA damage, cell proliferation, stem cell maintenance, and cell death in different cancer types. ΔNp63α is the dominantly expressed isoform of p63 in squamous cell carcinomas, playing a critical role in tumorigenesis [3, 4]. However, the functional roles of ΔNp63α in ESCC have not been fully elucidated. Our results have revealed that ΔNp63α is highly expressed and up-regulated in ESCC. We have shown that ΔNp63α protein expression plays an oncogenic role in ESCC cells, depletion of which inhibits in vitro cell proliferation and colony formation and greatly suppresses in vivo tumor growth, in a panel of ESCC cell lines and our latest patient-derived organoid cultures, potentially in a differentiation-dependent manner. Glycolysis pathway and two novel downstream signaling pathways of ΔNp63α, MYC/4EBP1 and AKT/NDRG1, are significantly suppressed upon ΔNp63α depletion in ESCC cell lines. Notably, xenografts of ΔNp63α-depleted human ESCC cells show elevated infiltrating cancer-associated fibroblasts (CAFs), which may contribute to tumor suppression by ΔNp63α depletion. These data not only shed light on the ΔNp63α functions and how they contribute to the ESCC tumorigenesis, but also unravel potential therapeutic benefits for ESCC patients in the future. Acknowledgements: We acknowledge DSMZ (German Collection of Microorganisms and Cell Culture) for the KYSE cell lines. We acknowledge the Research Grants Council Theme-Based Research Scheme grant T12-701/17-R to MLL. References [1] Chen, W., et al., Cancer statistics in China, 2015. CA Cancer J Clin, 2016. 66(2): p. 115-32. [2] Peng, L., et al., CCGD-ESCC: A Comprehensive Database for Genetic Variants Associated with Esophageal Squamous Cell Carcinoma in Chinese Population. Genomics Proteomics Bioinformatics, 2018. 16(4): p. 262-268. [3] Fukunishi, N., et al., Induction of DeltaNp63 by the newly identified keratinocyte-specific transforming growth factor beta Signaling Pathway with Smad2 and IkappaB Kinase alpha in squamous cell carcinoma. Neoplasia, 2010. 12(12): p. 969-79. [4] Moses, M.A., et al., Molecular Mechanisms of p63-Mediated Squamous Cancer Pathogenesis. Int J Mol Sci, 2019. 20(14). Citation Format: Shan Shan So, Valen Z. Yu, Simon Y. Law, Maria L. Lung. Functional and mechanistic characterization of ΔNp63α in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5835.
Abstract 120: HIF-1α regulation by Smurf2-mediated protein degradation in a VHL-independent manner
Authors: Shuai Zhao, Wafik S. El-Deiry
Journal: Cancer Research (2022)

Abstract HIF-1α is the main mediator of hypoxic response in cells and contributes to angiogenesis, metastasis and therapy resistance in cancer. The canonical pathway of HIF-1α degradation in normoxia is through the Von Hippel-Lindau (VHL) E3 ubiquitin ligase. We previously found that knockdown of CDK4 decreased HIF-1α expression in a VHL-independent manner. To explore the mechanism of CDK4-induced HIF-1α stabilization, we performed a proteomic analysis on HIF-1α-interacting proteins with palbociclib treatment, a bioinformatic prediction of HIF-1α-targeting E3 ubiquitin ligases and identified SMAD specific E3 ubiquitin protein ligase 2 (Smurf2) to be involved in a non-canonical HIF-1α regulation mechanism. Overexpression of Smurf2 enhanced the ubiquitination of HIF-1α and reduced expression of HIF-1α in HCT116 colorectal cancer cells. Smurf2 overexpression downregulated HIF-1α target gene SLC2A1 but not HIF1A mRNA level in hypoxia. Knockdown of SMURF2 increased HIF-1α expression in normoxia even when CDK4 was knocked-down. TCGA analysis showed correlation between high SMURF2 mRNA and better prognosis in kidney renal clear cell carcinoma (KIRC). In KIRC, VHL loss is a frequent mutational event that leads to high constitutive expression of HIF-1α and HIF-2α. Thus, we investigated a role for Smurf2 in HIF regulation in this cancer type. Overexpression of Smurf2 suppressed HIF-1α expression in RCC4 VHL-deficient clear cell renal cancer line in normoxia. Knockdown of SMURF2 increased HIF-1α expression in RCC4 cells. Treatment of RCC4 cells with Smurf2 inhibitor Heclin also increased HIF-1α expression in normoxia. HIF-2α expression was reduced upon Smurf2 overexpression in RCC4 cells under normoxia and in SW480 colorectal cancer cells under hypoxia. In summary, Smurf2 mediates VHL-independent HIF-1α degradation, which provides new insights for HIF-1α targeting in cancers especially with VHL deficiency, and targeting of Smurf2 to increase HIF activity may have functional consequences in non-neoplastic disorders. Citation Format: Shuai Zhao, Wafik S. El-Deiry. HIF-1α regulation by Smurf2-mediated protein degradation in a VHL-independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 120.